Pyrazolo[3,4-e]benzoxazoles for the treatment of glaucoma

ABSTRACT

Pyrazolo[3,4-e]benzoxazoles and analogues thereof for lowering intraocular pressure and treating glaucoma are disclosed.

RELATED APPLICATIONS

This application claims priority form U.S. patent application Ser. No.60/529,531, filed Dec. 15, 2003.

BACKGROUND OF THE INVENTION

The present invention relates to the use of pyrazolo[3,4-e]benzoxazolesand analogues thereof for lowering and controlling normal or elevatedintraocular pressure (IOP) and for treating glaucoma.

The disease state referred to as glaucoma is characterized by apermanent loss of visual function due to irreversible damage to theoptic nerve. The several morphologically or functionally distinct typesof glaucoma are typically characterized by elevated IOP, which isconsidered to be causally related to the pathological course of thedisease. Ocular hypertension is a condition wherein intraocular pressureis elevated but no apparent loss of visual function has occurred; suchpatients are considered to be at high risk for the eventual developmentof the visual loss associated with glaucoma. If glaucoma or ocularhypertension is detected early and treated promptly with medicationsthat effectively reduce elevated intraocular pressure, loss of visualfunction or its progressive deterioration can generally be ameliorated.Drug therapies that have proven to be effective for the reduction ofintraocular pressure include both agents that decrease aqueous humorproduction and agents that increase the outflow facility. Such therapiesare in general administered by one of two possible routes, topically(direct application to the eye) or orally.

There are some individuals who do not respond well when treated withcertain existing glaucoma therapies. There is, therefore, a need forother topical therapeutic agents that control IOP.

Serotonergic 5-HT_(1A) agonists have been reported as beingneuroprotective in animal models and many of these agents have beenevaluated for the treatment of acute stroke among other indications.This class of compounds has been mentioned for the treatment of glaucoma(lowering and controlling IOP), see e.g., WO 98/18458 (DeSantis, et al.)and EP 0771563A2 (Mano, et al.). Osborne, et al. (Ophthalmologica, Vol.210:308-314, 1996) teach that 8-hydroxydipropylaminotetralin (8-OH-DPAT)(a 5-HT_(1A) agonist) reduces IOP in rabbits. Wang, et al. (Current EyeResearch, Vol. 16(8):769-775, August 1997, and IVOS, Vol. 39(4), S488,March, 1998) indicate that 5-methylurapidil, an α_(1A) antagonist and5-HT_(1A) agonist lowers IOP in the monkey, but attribute the IOP effectto its α_(1A) receptor activity. Also, 5-HT_(1A) antagonists aredisclosed as being useful for the treatment of glaucoma (elevated IOP)(e.g., WO 92/0338, McLees). Furthermore, DeSai, et al. (WO 97/35579) andMacor, et al. (U.S. Pat. No. 5,578,612) relate to the use of 5-HT₁ and5-HT_(1-like) agonists for the treatment of glaucoma (elevated IOP).These anti-migraine compounds, e.g., sumatriptan and naratriptan andrelated compounds, are 5-HT_(1B,D,E,F) agonists.

It has been found that serotonergic compounds which possess agonistactivity at 5-HT₂ receptors effectively lower and control normal andelevated IOP and are useful for treating glaucoma, see U.S. Pat. No.6,664,286 incorporated in its entirety by reference herein. Compoundsthat act as agonists at 5-HT₂ receptors are well known and have shown avariety of utilities, primarily for disorders or conditions associatedwith the central nervous system (CNS). U.S. Pat. No. 5,494,928 relatesto certain 2-(indol-1-yl)-ethylamine derivatives that are 5-HT_(2C)agonists for the treatment of obsessive compulsive disorder and otherCNS derived personality disorders. U.S. Pat. No. 5,571,833 relates totryptamine derivatives that are 5-HT₂ agonists for the treatment ofportal hypertension and migraine. U.S. Pat. No. 5,874,477 relates to amethod for treating malaria using 5-HT_(2A/2C) agonists. U.S. Pat. No.5,902,815 relates to the use of 5-HT_(2A) agonists to prevent adverseeffects of NMDA receptor hypo-function. WO 98/31354 relates to 5-HT_(2B)agonists for the treatment of depression and other CNS conditions. WO00/12475 relates to indoline derivatives, and WO 00/12510 and WO00/44753 relate to certain indole derivatives as 5-HT_(2B) and 5-HT_(2C)receptor agonists for the treatment of a variety of disorders of thecentral nervous system, but especially for the treatment of obesity. WO00/35922 relates to certain pyrazino[1,2-a]quinoxaline derivates as5-HT_(2C) agonists for the treatment of obsessive compulsive disorder,depression, eating disorders, and other disorders involving the CNS. WO00/77002 and WO 00/77010 relate to certain substituted tetracyclicpyrido[4,3-b]indoles as 5-HT_(2C) agonists with utility for thetreatment of central nervous system disorders including obesity,anxiety, depression, sleep disorders, cephalic pain, and social phobiasamong others. Agonist response at the 5-HT_(2A) receptor is reported tobe the primary activity responsible for hallucinogenic activity, withsome lesser involvement of the 5-HT_(2C) receptor possible[Psychopharmacology, Vol. 121:357, 1995].

U.S. Pat. No. 5,561,150 relate to certain tricyclic pyrazole derivativecompounds which are identified as being 5-HT_(2C) agonists for thetreatment of CNS diseases and are primarily directed to lipophilicanalogs that have a high probability of entering the brain. Similarly,U.S. Pat. No. 6,245,796 relates to tricyclic 5-HT_(2C) agonists for thetreatment of CNS diseases. This patent includes claims to certainsubstituted pyrazolo[3,4-e]benzoxazoles though no specific examples areprovided. All the patents and publications mentioned above andthroughout are incorporated in their entirety by reference herein.

5-Hyroxytryptamine (serotonin) does not cross the blood-brain barrierand enter the brain. However, in order to increase brain serotoninlevels the administration of 5-hydroxy-tryptophan can be employed. Thetransport of 5-hydroxy-tryptophan into the brain readily occurs, andonce in the brain 5-hydroxy-tryptophan is rapidly decarboxylated toprovide serotonin.

Accordingly, there is a need to provide new compounds which avoid thedisadvantages described above and which provide increased chemicalstability and a desired length of therapeutic activity, for instance, indecreasing intraocular pressure and treating glaucoma.

SUMMARY OF THE PRESENT INVENTION

A feature of the present invention is to provide novel compounds whichare 5-HT₂ agonists.

Another feature of the present invention is to provide compounds whichhave increased chemical stability and which are useful in lowering andcontrolling normal or elevated intraocular pressure and/or treatingglaucoma.

Another feature of the present invention is to provide compounds whichprovide a desired level of therapeutic activity in lowering andcontrolling normal or elevated intraocular pressure and/or treatingglaucoma.

Additional features and advantages of the present invention will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of thepresent invention. The objectives and other advantages of the presentinvention will be realized and attained by means of the elements andcombinations particularly pointed out in the description and appendedclaims.

To achieve these and other advantages, and in accordance with thepurposes of the present invention, as embodied and broadly describedherein, the present invention relates to a compound having the FormulaI:

and being described more fully below.

The present invention further relates to pharmaceutical compositionscontaining at least one compound of Formula I.

The present invention further relates to methods to lower and/or controlnormal or elevated intraocular pressure by administering an effectiveamount of a composition containing a compound having Formula I asdescribed above.

The present invention also relates to a method for treating glaucomawhich involves administering an effective amount of a compositioncontaining a compound having Formula I as described above.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are intended to provide a further explanation of the presentinvention, as claimed.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention relates to a variety of compounds which are usefulaccording to the present invention. These compounds are represented bythe following Formula I:

Wherein R¹ and R² are independently chosen from hydrogen, C₁₋₄alkyl;

-   -   R³ is selected from hydrogen, C₁₋₄alkyl, or R² and R³ can        complete a pyrrolidine or piperidine ring, which can be        substituted with C₁₋₄alkyl;    -   R⁴ is hydrogen, C₁₋₄alkyl, or when Y is carbon R⁴ can also be        halogen;    -   R⁵ and R⁶ are independently chosen from hydrogen, halogen,        C₁₋₆alkyl, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfoxide,        nitrile, C₁₋₆alkyl substituted with halogen;    -   R⁷is chosen from C═OR⁹, S(O)_(m)R¹⁰, NR¹—(C═O)—R¹¹,    -   C₁₋₆alkyl substituted with: hydroxyl, C₁₋₆alkoxy, NR¹²R¹³, CO₂H,        CO₂C₁₋₆alkyl, C(═O)NR¹²R¹³ or S(O)_(m)NR¹²R¹³, or a saturated or        unsaturated 5 or 6-membered heterocyclic ring which can contain        1-4 heteroatoms selected from N, O, or S and can be        unsubstituted or substituted with C₁₋₄alkyl;    -   or R⁷ can be chosen from a heterocyclic ring selected from        oxazol-2-yl, 4,5-dihydro-oxazol-2-yl,        5,6-dihydro-[1,3]oxazin-2-yl, thiazol-2-yl,        4,5-dihydro-thiazol-2-yl, benzoxazol-2-yl, benzothiazol-2-yl,        imidazol-2-yl, imidazolidin-2-yl, [1,2,4]oxadiazol-5-yl,        [1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-5-yl, or        [1,2,4]thiadiazol-3-yl which can be unsubstituted or substituted        with C₁₋₄alkyl;    -   but R⁷ cannot be hydrogen, lower alkyl, hydroxyl, lower alkoxy,        amino, mono- or di-loweralkyl amino, lower alkanoylamino, or        halogen;    -   R⁹ is chosen from hydroxyl, C₁₋₆alkoxy, NR¹⁴R¹⁵, C₁₋₆alkyl, or        C₂₋₆alkyl substituted with hydroxyl, C₁₋₆alkoxy, NR¹²R¹³, CO₂H,        CO₂C₁₋₆alkyl, S(O)_(m)NR¹²R¹³, halogen, or a heterocyclic ring        selected from pyrrolidin-2-yl, imidazo-2-yl, imidazo-4-yl,        morpholin-3-yl, oxazolyl, isoxazolyl, thiazolyl, or tetrazolyl,        which can be unsubstituted or substituted with C₁₋₄alkyl;    -   R¹⁰ is chosen from NR¹²R¹³, C₁₋₆alkyl, or C₂₋₆alkyl substituted        with hydroxyl, C₁₋₆alkoxy, NR¹¹R¹², CO₂H, CO₂C₁₋₆alkyl;    -   R¹¹ is C₁₋₆alkyl substituted with hydroxyl, C₁₋₆alkoxy, or a        saturated or unsaturated 5 or 6-membered heterocyclic ring which        can contain 1-4 heteroatoms selected from N, O, or S and can be        unsubstituted or substituted with C₁₋₄alkyl;    -   R¹² and R¹³ are independently selected from hydrogen, C₁₋₆alkyl,        C₂₋₆alkyl substituted with hydroxyl, C₁₋₆alkoxy, or halogen, or        R¹², R¹³, and the intervening nitrogen atom can form a        heterocyclic ring selected from morpholine, thiomorpholine,        thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, azetidine,        pyrrolidine, piperidine, piperazine, unsubstituted or        substituted with C₁₋₄alkyl or C₁₋₄alkyl substituted with hydroxy        or C₁₋₄alkoxy;    -   R¹⁴ and R¹⁵ are independently selected from hydrogen, C₁₋₆alkyl,        hydroxyl, C₁₋₆alkoxy, C₂₋₆alkyl substituted with hydroxyl,        C₁₋₆alkoxy, halogen or a heterocyclic ring selected from        pyrrolidin-2-yl, imidazo-2-yl, imidazo-4-yl, morpholin-3-yl,        oxazolyl, isoxazolyl, thiazolyl, tetrazolyl, which can be        unsubstituted or substituted with C₁₋₄alkyl, or R¹⁴, R¹⁵, and        the intervening nitrogen atom can form a heterocyclic ring        selected from morpholine, thiomorpholine, thiomorpholine        1-oxide, thiomorpholine 1,1-dioxide, azetidine, pyrrolidine,        piperidine, piperazine, unsubstituted or substituted with        C₁₋₄alkyl or C₁₋₄alkyl substituted with hydroxy or C₁₋₄alkoxy;    -   =a double or single bond in the oxazole ring;    -   when R¹⁶ is no atom,        is a double bond, and when        is a single bond, R⁷ is Q, where Q is oxygen, sulfur, or NR¹        attached to the oxazole ring by a double bond;    -   m is 0-2;    -   A is N or CH;    -   X and Y are either N or C, wherein X and Y cannot be the same;        and the dashed bonds in this ring denote a suitably appointed        single and double bond;        Pharmaceutically acceptable salts and solvates, and prodrug        forms of the compounds of Formula I are also part of the present        invention. Certain compounds of Formula I can contain one or        more chiral centers. The present invention contemplates all        enantiomers, diastereomers, and mixtures thereof.

In the above definitions, the total number of carbon atoms in asubstituent group is indicated by the C_(i-j) prefix where the numbers iand j define the number of carbon atoms.. This definition includesstraight chain, branched chain, and cyclic alkyl or (cyclic alkyl)alkylgroups. A substituent may be present either singly or multiply whenincorporated into the indicated structural unit. For example, thesubstituent halogen, which means fluorine, chlorine, bromine, or iodine,would indicate that the unit to which it is attached may be substitutedwith one or more halogen atoms, which may be the same or different.

Preferred are compounds of Formula I wherein:

A═N;

X═N;

Y═C; and

in the oxazole ring is a double bond; and

pharmaceutically acceptable salts, solvates and prodrugs thereof.

Of the preferred compounds, most preferred are those compounds ofFormula I wherein:

R¹ and R²═H.

Among these compounds, especially preferred are the compounds of FormulaI wherein:

R³=methyl.

The term “alkanoylamino” represents a group that is linked by an aminoatom that is connected to a carbon atom has a double bond to an oxygengroup and a single bond to a carbon atom or hydrogen atom.

The term “acyloxy” represents a group that is linked by an oxygen atomthat is connected to a carbon that has a double bond to an oxygen atomand single bond to another carbon atom.

The term “alkenyl” includes straight or branched chain hydrocarbongroups having 1 to 15 carbon atoms with at least one carbon-carbondouble bond. The chain hydrogens may be substituted with other groups,such as halogen. Preferred straight or branched alkeny groups include,allyl, 1-butenyl, 1-methyl-2-propenyl and 4-pentenyl.

The term “alkoxy” represents an alkyl group attached through an oxygenlinkage.

The term “alkyl” includes straight, branched or cyclic aliphatichydrocarbon groups that are saturated and have 1 to 15 carbon atoms. Thealkyl groups may be substituted with other groups, such as halogen,hydroxyl or alkoxy. Preferred straight or branched alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl and t-butyl.

The term “alkylamino” represents an alkyl group attached through anitrogen linkage.

The term “alkynyl” includes straight or branched chain hydrocarbongroups having 1 to 15 carbon atoms with at least one carbon-carbontriple bond. The chain hydrogens may be substituted with other groups,such as halogen. Preferred straight or branched alkynyl groups include,2-propynyl, 2-butynyl, 3-butynyl, 1 -methyl-2-propynyl and 2-pentynyl.

The term “aryl” refers to carbon-based rings which are aromatic. Therings may be isolated, such as phenyl, or fused, such as naphthyl. Thering hydrogens may be substituted with other groups, such as loweralkyl, or halogen.

The term “carbonyl” represents a group that has a carbon atom that has adouble bond to an oxygen atom.

The term “carbonylalkoxy” represents a group that is linked by a carbonatom that has a double bond to an oxygen atom and a single bond to analkoxy group.

The term “cationic salt moiety” includes alkali and alkaline earth metalsalts as well as ammonium salts.

The term “carbonyloxyl” represents a group that is linked by a carbonatom that has a double bond to an oxygen atom and a single bond to asecond oxygen atom.

The term “cycloalkyl” includes straight or branched chain, saturated orunsaturated aliphatic hydrocarbon groups which connect to form one ormore rings, which can be fused or isolated. The rings may be substitutedwith other groups, such as halogen, hydroxyl or lower alkyl. Preferredcycloalkyl groups include cyclopropyl, cyclobutyl, cylopentyl andcyclohexyl.

The term “dialkylamino” represents two alkyl groups attached through anitrogen linkage.

The term “halogen” and “halo” represents fluoro, chloro, bromo, or iodo.

The term “heteroaryl” refers to aromatic hydrocarbon rings which containat least one heteroatom such as O, S, or N in the ring. Heteroaryl ringsmay be isolated, with 5 to 6 ring atoms, or fused, with 8 to 10 atoms.The heteroaryl ring(s) hydrogens or heteroatoms with open valency may besubstituted with other groups, such as lower alkyl or halogen. Examplesof heteroaryl groups include imidazole, pyridine, indole, quinoline,furan, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, anddihydrobenzindole.

The term “lower alkyl” represents alkyl groups containing one to sixcarbons (C₁-C₆).

Synthesis

Compounds of Formula I can be prepared by using one of several syntheticprocedures. Pg denotes a suitable protective group to assure that aparticular atom is not modified during the indicated chemical reaction.

Using the procedures described in Schemes 1-3 (above), the Examples 1-4(below), and well known procedures, one skilled in the art can preparethe compounds disclosed herein. Preferred compounds according to thepresent invention are those set forth in Table 1 below.

Example 1(S)-2-(7-Methoxy-1H-pyrazolo[3,4-e]benzoxazol-1-yl)-1-methylethylamine

Step A. [(S)-2-(6-Hydroxy-indazol-1-yl)-l-methylethyl]-carbamic acidbenzyl ester

1-((S)-2-Aminopropyl)-1H-indazol-6-ol [prepared in accordance withcommonly owned WO 02/098862A1, the contents of which are by thisreference incorporated herein] (2.00 g, 10.5 mmol) was suspended in THF(20 mL) and saturated aqueous sodium bicarbonate (10 mL) and benzylchloroformate (1.50 mL, 15 mol) were added. The mixture was stirred atroom temperature until the starting amine dissolved. Saturated aqueoussodium bicarbonate (150 mL) was added and the reaction mixture extractedwith ethyl acetate (3×150 mL). The combined organic layers were dried(magnesium sulfate), filtered, and evaporated to give a tan foam (2.65g, 78%) which was pure by LC/MS (+APCI) m/z 326 (M+H⁺).

Step B: Benzyl (S)-2-(7-bromo-6-hydroxy-1H-indazol-1-yl)-1-methylethylcarbamate

A solution of benzyl(S)-2-(6-hydroxy-1H-indazol-1-yl)-1-methylethylcarbamate (3.00 g, 9.23mmol) from Step A in tetrahydrofuran (30 mL) was cooled in an ice bath,small portions of N-bromosuccinimide (1.64 g, 9.23 mmol) were added andthe mixture was stirred for a few minutes followed by the addition of asaturated aqueous solution of sodium sulfite (150 mL). The mixture wasextracted with ethyl acetate (2×100 mL). The combined extracts weredried over magnesium sulfate, filtered, and evaporated to a white solid(3.76 g): mp 40° C.; LC/MS m/z 404/406.

Step C: Benzyl(S)-2-(6-hydroxy-7-nitro-1H-indazol-1-yl)-1-methylethylcarbamate

A solution of the product from Step B (3.76 g, 9.3 mmol) intetrahydrofuran (20 mL) and acetic acid (10 mL) was cooled in an icebath, sodium nitrate (1.93 g, 27.9 mmol) was added and the reactionmixture was stirred for 1 h followed by warming to room temperature andstirring for one hour. Water (150 mL) was added to the reaction mixture,which was extracted with ethyl acetate (2×100 mL). The combined extractswere washed with a saturated aqueous solution of sodium bicarbonate(2×100 m), dried over magnesium sulfate, filtered, and evaporated to anoil (2.87 g). This residue was purified by chromatography (silica gel,hexane/ethyl acetate) to give a tan foam (2.44 g, 71%): LC/MS m/z 371.This was used in the next reaction without further purification.

Step D: Benzyl(S)-2-(7-amino-6-hydroxy-1H-indazol-1-yl)-1-methylethylcarbamate

The product from Step C (0.20 g, 0.54 mmol) was combined with aceticacid (5 mL), water (5 mL), and iron powder (0.30 g mmol) and stirred atroom temperature for 1 h. The reaction mixture was filtered andevaporated to a dark oil (0.47 g) which was was used in the nextreaction: LC/MS m/z 341.

Step E: Benzyl (S)-2-(7-methoxy-1H-pyrazolo[3,4-e]benzoxazol-1-yl)-1-methylethylcarbamate

The product from Step D (0.47 g) was combined with tetramethylorthocarbonate (15 mL), p-toluenesulfonic acid hydrate (10 mg) and themixture was stirred at room temperature for 1 h. The reaction wasquenched with triethylamine (1 ml) and the reaction mixture wasevaporated to a residue which was purified by chromatography (silicagel, hexane/ethyl acetate gradient) to give a colorless oil (60 mg):LC/MS m/z 381.

Step F: (S)-2-(7-Methoxy-1H-pyrazolo[3,4-e]benzoxazol-1-yl)-1-methylethylamine

To a solution of the product from Step E (60 mg,0.157 mmol) in methanol(10 mL) was added 10% palladium-on-carbon (20 mg) and the mixture wasstirred under an atmosphere of hydrogen at room temperature for 18 h.The reaction mixture was filtered and evaporated to a colorless oil (30mg): LC/MS m/z 247.

Example 2 (S)-2-[7-(Methoxymethyl)-1H-pyrazolo[3,4-e]benzoxazol- 1 -yl]-1 -methylethylamine

Step A: 1 -[(R)-2-hydroxypropyl]-7-nitroso-1H-indazol-6-ol

To a solution of 1-[(R)-2-hydroxypropyl]-1H-indazol-6-ol (2.0 g, 1.04mmol) in acetic acid (20 mL) was added sodium nitrite (0.72 g, 10.4 mol)and the mixture was stirred at room temperature for 1 hour. Water (200mL) was added and the mixture was extracted with ethyl acetate (2×200mL). The combined extracts were washed with water (200 mL), and asaturated aqueous solution of sodium bicarbonate (200 mL), dried overmagnesium sulfate, filtered and evaporated to a residue which waspurified by chromatography (silica gel, hexane/ethyl acetate gradient)to give a red solid (1.07 g, 47%): LC/MS m/z 222.

Step B:(R)-1-[7-(Methoxymethyl)-1H-pyrazolo[3,4-e]benzoxazol-1-yl]propan-2-ol

A solution of the product from Step A (1.05 g, 4.75 mol) intetrahydrofuran (50 mL) containing 10% palladium-on-carbon (0.1 g) wasstirred under an atmosphere of hydrogen at room temperature for 18hours. The reaction mixture was filtered, pyridine (1.0 mL, 12.3 mol)and methoxy acetyl chloride (0.43 mL, 4.75 mol) were added, and thismixture was stirred at room temperature. More pyridine (5.0 mL) wasadded and the reaction mixture was stirred at room temperature for 20minutes followed by the addition of 4-dimethylaminopyridine (0.1 g);this mixture was heated at 60 ° C. for 3 hours followed by removal ofsolvents by heating at 220 ° C. for 30 minutes. The resulting darkliquid was purified by chromatography (silica gel, hexane/ethyl acetategradient) to give a yellow oil (200 mg, 16%): LC/MS m/z 262.

Step C:1-[(S)-2-Azidopropyl]-7-(methoxymethyl)-1H-pyrazolo[3,4-e]benzoxazole

A solution of the product from Step B (0.20 g, 0.77 mmol intetrahydrofuran (10 mL) was cooled (ice bath), triethylamine (0.43 mL,3.06 mmol) and methanesulfonic anhydride (0.24 g, 1.38 mmol) were addedand the mixture was stirred at 0 ° C for 20 minutes. Sodium azide (0.50g, 7.66 mmol) was added to the reaction mixture, which was evaporated toa residue that was dissolved in dimethyl sulfoxide (10 mL) and heated at90-100 ° C. for 2 hours. The reaction mixture was cooled to roomtemperature, water (200 mL) was added, and the mixture was extractedwith ethyl acetate (2×100 mL). The combined extracts were dried(magnesium sulfate), filtered, and evaporated to give a residue whichwas purified by chromatography (silica gel, hexane/ethyl acetate) togive a yellow oil (80 mg, 37%): LC/MS m/z 287.

Step D: (S)-2-[7-(Methoxymethyl)-1H-pyrazolo[3,4-e]benzoxazo-1-yl]-1-methylethylamine

A solution of the product of Step C (80 mg, 0.28 mmol) in methanol (10mL) containing 10% palladium-on-carbon (10 mg) was stirred under anatmosphere of hydrogen for 18 hours. The reaction mixture was filteredand evaporated to give a yellow solid (60 mg, 83%): mp 40-43 ° C.; LC/MSm/z 261.

Example 3 1-[(S)-2-Aminopropyl]-1H-pyrazolo[3,4-e]benzoxazole-7-carboxylic acid amide

Step A: 7-Bromo-1-[(R)-2-hydroxypropyl]-1H-indazol-6-ol

A solution of 1-[(R)-2-hydroxypropyl]-1H-indazol-6-ol (4.76 g, 24.8mmol) in tetrahydrofuran (50 mL), cooled in an ice bath, added smallportions of N-bromosuccinimide (4.41 g, 24.8 mmol) and stirred while thereaction warmed to room temperature. The reaction was quenched withaqueous saturated sodium sulfite (100 mL) and extracted with ethylacetate (100 mL). The combined extracts were dried (magnesium sulfate),filtered and evaporated to a yellow solid (7 g): mp 134-136° C.; LC/MSm/z 271/273.

Step B:1-[(R)- 2-Hydroxypropyl]-7-nitro-1-H-indazol-6-ol

A solution of the product from Step A (6.99 g, 24.8 mmol) in a mixtureof tetrahydrofuran (20 mL) and acetic acid (20 mL) was cooled in an icebath. Sodium nitrite (5.13 g, 74.4 mol) was added and the mixture wasstirred for one hour, warmed to room temperature and stirring continuedfor one hour. Water (200 mL) was added to the reaction mixture, whichwas extracted with ethyl acetate (200 mL). The organic layer was washedwith aqueous saturated sodium bicarbonate (100 mL, to pH 7), dried(magnesium sulfate), filtered and evaporated to an oil (4.75 g).Purification by chromatography gave a bright yellow solid (2.96 g, 50%):mp 70-74° C.; LC/MS m/z 238.

Step C: 7-Amino-1-[(R)-2-hydroxypropyl]-1H-indazol-6-ol

To a solution of the product from Step B (1.84 g, 7.76 mmol) in methanol(20 mL) was added palladium-on-carbon (100 mg) and this mixture wasstirred under a hydrogen atmosphere at room temperature for 4 h. Thereaction mixture was filtered (avoiding air) and evaporated to acolorless oil: LC/MS m/z 208. This oil was immediately carried into thenext step.

Step D: 1-[(R)-2-Hydroxypropyl]-1H-pyrazolo[3,4-e]benzoxazole-7-carboxylic acid amide

To a solution of the product from Step C (1.61 g, 7.76 mmol) in methanol(20 mL) was added dimethyl oxalate (9.16 g, 77.6 mmol), p-toluenesulfonic anhydride hydrate (50 mg), and the mixture was heated todistill off liquids with a bath temperature of 120° C. for 5 h. The darkresidue was treated with methanolic ammonia (7 M, 22 mL, 0.15 mol) andheated at reflux temperature for 1 h. Additional ammonia (7 M inmethanol, 20 mL) was added and heating continued for another hour. Thereaction mixture was cooled to room temperature, filtered, andevaporated to a brown solid that was purified by chromatography to givea tan solid (0.91 g, 45%): LC/MS m/z 279.

Step E: 1-[(S)-2-Azidopropyl]-1H-pyrazolo[3,4-e]benzoxazole-7-carboxylic acid amide

To a suspension of the product-from Step D (0.90 g, 3.45 mmol) intetrahydrofuran (20 mL) was added triethylamine (1.93 mL, 13.9 mmol);this mixture was cooled (ice bath), methane sulfonic anhydride (1.20 g,6.92 mmol) was added, and the mixture was stirred for 20 minutes. Sodiumazide (2.25 g, 34.6 mmol) was added and the mixture was evaporated to aresidue which dissolved in dimethyl sulfoxide (20 mL) and heated at 90°C. for 2.5 hours. The reaction mixture was cooled to room temperature,water (200 mL) was added, and the mixture was extracted with ethylacetate (2×100 mL). The combined extracts were washed with water (100mL), dried (magnesium sulfate), filtered, and evaporated to solid (0.97g). This residue was purified by chromatography (silica gel, ethylacetate gradient) and recrystallized from methanol and ethyl acetate togive a colorless solid (0. 18 g, 18%): mp 162-164° C.; LC/MS m/z 286.

Step F: 1-[(S)-2-Aminopropyl]-1H-pyrazolo[3,4-e]benzoxazole-7-carboxylicacid amide

To a solution of the product from Step E (0.18 g, 0.631 mmol) inmethanol (10 mL) was added 10% palladium-on-carbon (20 mg). This mixturewas maintained under an atmosphere of hydrogen at room temperature forthree days. The reaction mixture was filtered and evaporated to a tansolid (0.16 g): mp 60-65° C.; LC/MS m/z 260. Analysis. Calculated forC₁₂H₁₃N₅O₂.0.5 CH₃0H: C, 54.54; H, 5.49; N, 25.44. Found: C, 54.79; H,5.35; N, 25.29.

Example 41-[(S)-2-Aminopropyl]-1H-pyrazolo[3,4-e]benzoxazole-7-carboxylic acidmethylamide

This compound was prepared in a manner essentially identical to thatdescribed in Example 3, but using a solution of methylamine in methanol(2 M) in Step D rather than a solution of ammonia in methanol, to givean amorphous foam (100 mg): LC/MS 274 m/z; ¹H NMR was consistent withthe assigned structure.

The compounds of the present invention can be used to lower and controlIOP including IOP associated with normotension glaucoma, ocularhypertension, and glaucoma in warm blooded animals including humans andother mammals. Since the treatment of glaucoma is preferably withcompounds that do not enter the CNS, relatively polar compounds that are5-HT₂ agonists are of particular interest. The compounds are preferablyformulated in pharmaceutical compositions which are preferably suitablefor topical delivery to the eye of the patient.

The compounds of this invention, Formula I, can be incorporated intovarious types of pharmaceutical compositions, such as ophthalmicformulations for delivery to the eye (e.g., topically, intracamerally,or via an implant). The compounds are preferably incorporated intotopical ophthahnic formulations for delivery to the eye. The compoundsmay be combined with ophthalmologically acceptable preservatives,viscosity enhancers, penetration enhancers, buffers, sodium chloride,and water to form an aqueous, sterile ophthalmic suspension or solution.Ophthalmic solution formulations may be prepared by dissolving acompound in a physiologically acceptable isotonic aqueous buffer.Further, the ophthalmic solution may include an ophthalmologicallyacceptable surfactant to assist in dissolving the compound. Furthermore,the ophthalmic solution may contain an agent to increase viscosity, suchas hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, orthe like, to improve the retention of the formulation in theconjunctival sac. Gelling agents can also be used, including, but notlimited to, gellan and xanthan gum. In order to prepare sterileophthalmic ointment formulations, the active ingredient is combined witha preservative in an appropriate vehicle, such as, mineral oil, liquidlanolin, or white petrolatum. Sterile ophthalmic gel formulations may beprepared by suspending the active ingredient in a hydrophilic baseprepared from the combination of, for example, carbopol-974, or thelike, according to the published formulations for analogous ophthalmicpreparations; preservatives and tonicity agents can be incorporated.

The compounds are preferably formulated as topical ophthalmicsuspensions or solutions, with a pH of about 5 to 8, and more preferablyabout 6.5 to about 7.5. The compounds will normally be contained inthese formulations in an amount 0.01% to 5% by weight, but preferably inan amount of 0.025% to 2% by weight. Thus, for topical presentation 1 to2 drops of these formulations would be delivered to the surface of theeye 1 to 4 times per day according to the discretion of a skilledclinician.

The compounds can also be used in combination with other agents fortreating glaucoma, such as, but not limited to, β-blockers (e.g.,timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol),carbonic anhydrase inhibitors (e.g., brinzolainide and dorzolamide), a,antagonists (e.g., nipradolol), α₂ agonists (e.g. iopidine andbrimonidine), miotics (e.g., pilocarpine and epinephrine), prostaglandinanalogs (e.g., latanoprost, travoprost, unoprostone, and compounds setforth in U.S. Pat. Nos. 5,889,052; 5,296,504; 5,422,368; and 5,151,444,“hypotensive lipids” (e.g., bimatoprost and compounds set forth in5,352,708), and neuroprotectants (e.g., compouids from U.S. Pat. No.4,690,931, particularly eliprodil and R-eliprodil, and appropriatecompounds from WO 94/13275, including memantine.

The compounds of the present invention preferably function as 5-HT₂agonists and preferably do not enter the CNS. Compounds having theability to be a 5-HT₂ agonist are beneficial for controlling IOP as wellas the treatment of glaucoma as shown in U.S. Pat. No. 6,664,286incorporated in its entirety by reference herein.

The compounds of the present invention preferably provide increasedchemical stability and preferably achieve the desired level oftherapeutic activity which includes a lowering or controlling of IOP.

The compounds of the present invention can be used in controlling orlowering IOP in warm blooded animals including humans. Preferably, aneffective amount of the compound is administered to the patient suchthat the IOP is controlled or lowered to acceptable levels. Furthermore,the compounds of the present invention can be used to treat glaucoma inwarm blooded animals, including humans, by administering an effectiveamount of the compound to a patient in need of such treatment to treatthe glaucoma. Pharmaceutically acceptable amounts of the compounds ofthe present invention will be readily understood by those skilled in theart to mean amounts sufficient to effect the desired therapy withouttoxicity or other deleterious effects on the patients' health. Examplesof such amounts include without limitation those amounts shown in theExamples.

Another embodiment of the present invention is a method of activating orbinding serotonin receptors, comprising administering an effectiveamount of at least one compound of the present invention to a patientusing an amount effective to activate or bind serotonin receptors, suchas, but not limited to, the dosage levels described herein.

The procedures described herein in Method 1 can be used to confirm acompound's 5-HT₂ binding affinity.

Method 1

5-HT₂ Receptor Binding Assay

To determine the affinities of serotonergic compounds at the 5-HT₂receptors, their ability to compete for the binding of the agonistradioligand [¹²⁵I]DOI to brain 5-HT₂ receptors is determined asdescribed below with minor modification of the literature procedure[Neuropharmacology, 26, 1803 (1987)]. Aliquots of post mortem rat orhuman cerebral cortex homogenates (400 μL) dispersed in 50 mM TrisHClbuffer (pH 7.4) are incubated with [¹²⁵I]DOI (80 μM final) in theabsence or presence of methiothepin (10 μM final) to define total andnon-specific binding, respectively, in a total volume of 0.5 mL. Theassay mixture is incubated for 1 hour at 23° C. in polypropylene tubesand the assays terminated by rapid vacuum filtration over Whatman GF/Bglass fiber filters previously soaked in 0.3% polyethyleneimine usingice-cold buffer. Test compounds (at different concentrations) aresubstituted for methiothepin. Filter-bound radioactivity is determinedby scintillation spectrometry on a beta counter. The data are analyzedusing a non-linear, iterative curve-fitting computer program [TrendsPharmacol. Sci., 16, 413 (1995)] to determine the compound affinityparameter. The concentration of the compound needed to inhibit the[¹²⁵I]DOI binding by 50% of the maximum is termed the IC₅₀ or K_(i)value.

Method 2

5-HT₂ Functional Assay: [Ca²⁺]_(i) Mobilization

The receptor-mediated mobilization on intracellular calcium ([Ca²⁺]_(i))was studied using the Fluorescence Imaging Plate Reader (FLIPR)instrument. Rat vascular smooth muscle cells, A7r5, were grown in anormal media of DMEM/10% FBS and 10 μg/mL gentamycin. Confluent cellmonolayers were trypsinized, pelleted, and re-suspended in normal media.Cells were seeded in a 50 μL volume at a density of 20,000 cells/well ina black wall, 96-well tissue culture plate and grown for 2 days.

On the day of the experiment, one vial of FLIPR Calcium Assay Kit dyewas re-suspended in 50 mL of a FLIPR buffer consisting of Hank'sBalanced Salt Solution (HBSS), 20 mM HEPES, and 2.5 mM probenecid, pH7.4. Cells were loaded with the calcium-sensitive dye by addition of anequal volume (50 μL) to each well of the 96-well plate and incubatedwith dye for 1h at 23° C.

Typically, test compounds were stored at 25 μM in 50% DMSO/50% Ethanolsolvent. Compounds were diluted 1:50 in 20% DMSO/20% Ethanol. For “hit”screening, compounds were further diluted 1:10 in FLIPR buffer andtested at a final concentration of 10 μM. For dose-response experiments,compounds were diluted 1:50 in FLIPR buffer and serially diluted 1:10 togive a 5- or 8-point dose-response curve.

The compound plate and cell plate were placed in the FLIPR instrument.At the beginning of an experimental run, a signal test was performed tocheck the basal fluorescence signal from the dye-loaded cells and theuniformity of the signal across the plate. The basal fluorescence wasadjusted between 8000-12000 counts by modifying the exposure time, thecamera F-stop, or the laser power. Instrument settings for a typicalassay were the following: laser power 0.3-0.6 W, camera F-stop F/2. andexposure time 0.4 sec. An aliquot (25 μL) of the test compound was addedto the existing 100 μL dye-loaded cells at a dispensing speed of 50μL/sec. Fluorescence data were collected in real-time at 1.0 secintervals for the first 60 secs and at 6.0 sec intervals for anadditional 120 secs. Responses were measured as peak fluorescenceintensity minus basal and where appropriate were expressed as apercentage of a maximum 5-HT-induced response. When the compounds weretested as antagonists against 10 μM 5-HT, they were incubated with thecells for 15 minutes prior to the addition of 5-HT.

The above procedures were used to generate the data shown in Table 1.TABLE 1 5-HT_(2A) Receptor Binding and Functional Data 5-HT_(2A) ExampleIC₅₀ (nM) EC₅₀ (nM) E_(max) (%) 1 8 352 72 2 6 174 88 3 445 72 4 19 90777

The following topical ophthalmic formulations are useful according tothe present invention administered 1-4 times per day according to thediscretion of a skilled clinician. Ingredients Amount (wt %) Compound ofany of Examples 1-4 0.01-2% Hydroxypropyl methylcellulose  0.5% Dibasicsodium phosphate (anhydrous)  0.2% Sodium chloride  0.5% Disodium EDTA(Edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkonium chloride0.01% Sodium hydroxide/Hydrochloric acid For adjusting pH to 7.3-7.4Purified water q.s. to 100%

Example 6

Ingredients Amount (wt %) Compound of any of Examples 1-4 0.01-2% Methylcellulose  4.0% Dibasic sodium phosphate (anhydrous)  0.2% Sodiumchloride  0.5% Disodium EDTA (Edetate disodium) 0.01% Polysorbate 800.05% Benzalkonium chloride 0.01% Sodium hydroxide/Hydrochloric acid Foradjusting pH to 7.3-7.4 Purified water q.s. to 100%

Example 7

Ingredients Amount (wt %) Compound of any of Examples 1-4 0.01-2%   Guargum  0.4-6.0% Dibasic sodium phosphate (anhydrous)  0.2% Sodium chloride 0.5% Disodium EDTA (Edetate disodium) 0.01% Polysorbate 80 0.05%Benzalkonium chloride 0.01% Sodium hydroxide/Hydrochloric acid Foradjusting pH to 7.3-7.4 Purified water q.s. to 100%

Example 8

Ingredients Amount (wt %) Compound of any of Examples 1-4 0.01-2% Whitepetrolatum and mineral oil and lanolin Ointment consistency Dibasicsodium phosphate (anhydrous)  0.2% Sodium chloride  0.5% Disodium EDTA(Edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkonium chloride0.01% Sodium hydroxide/Hydrochloric acid For adjusting pH to 7.3-7.4

Other embodiments of the present invention will be apparent to thoseskilled in the art from consideration of the present specification andpractice of the present invention disclosed herein. It is intended thatthe present specification and examples be considered as exemplary onlywith a true scope and spirit of the invention being indicated by thefollowing claims and equivalents thereof.

1-9. (canceled)
 10. A compound of Formula I:

Wherein R¹ and R² are independently chosen from hydrogen, C₁₋₄alkyl; R³is selected from hydrogen, C₁₋₄alkyl, or R² and R³ can complete apyrrolidine or piperidine ring, which can be substituted with C₁₋₄alkyl;R⁴ is hydrogen, C₁₋₄alkyl, or when Y is carbon R⁴ can also be halogen;R⁵ and R⁶ are independently chosen from hydrogen, halogen, C₁₋₆-alkyl,C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, C₁₋₆-alkylsulfoxide, nitrile,C₁₋₆-alkyl substituted with halogen; R⁷ is chosen from C═OR⁹,S(O)_(m)R¹⁰, NR¹—(C═O)—R¹¹, C₁₋₆-alkyl substituted with: hydroxyl,C₁₋₆alkoxy, NR¹²R¹³, CO₂H, CO₂C₁₋₆alkyl, C(═O)NR¹²R¹³ orS(O)_(m)NR¹²R¹³, or a saturated or unsaturated 5 or 6-memberedheterocyclic ring which can contain 1-4 heteroatoms selected from N, O,or S and can be unsubstituted or substituted with C₁₋₄alkyl; or R⁷ canbe chosen from a heterocyclic ring selected from oxazol-2-yl,4,5-dihydro-oxazol-2-yl, 5,6-dihydro-[1,3]oxazin-2-yl, thiazol-2-yl,4,5-dihydro-thiazol-2-yl, benzoxazol-2-yl, benzothiazol-2-yl,imidazol-2-yl, imidazolidin-2-yl, [1,2,4]oxadiazol-5-yl,[1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-5-yl, or [1,2,4]thiadiazol-3-ylwhich can be unsubstituted or substituted with C₁₋₄alkyl; but R⁷ cannotbe hydrogen, lower alkyl, hydroxyl, lower alkoxy, amino, mono- ordi-loweralkyl amino, lower alkanoylamino, or halogen; R⁹ is chosen fromhydroxyl, C₁₋₆alkoxy, NR¹⁴R¹⁵, C₁₋₆alkyl, or C₂₋₆alkyl substituted withhydroxyl, C₁₋₆alkoxy, NR¹²R¹³, CO₂H, CO₂C₁₋₆alkyl, S(O)_(m)NR¹²R¹³,halogen, or a heterocyclic ring selected from pyrrolidin-2-yl,imidazo-2-yl, imidazo4-yl, morpholin-3-yl, oxazolyl, isoxazolyl,thiazolyl, or tetrazolyl, which can be unsubstituted or substituted withC₁₋₄alkyl; R¹⁰ is chosen from NR¹²R¹³, C₁₋₆alkyl, or C₂₋₆alkylsubstituted with hydroxyl, C₁₋₆alkoxy, NR¹¹R¹², CO₂H, CO₂C₁₋₆alkyl; R¹¹is C₁₋₆alkyl substituted with hydroxyl, C₁₋₆alkoxy, or a saturated orunsaturated 5 or 6-membered heterocyclic ring which can contain 1-4heteroatoms selected from N, O, or S and can be unsubstituted orsubstituted with C₁₋₄alkyl; R¹² and R³ are independently selected fromhydrogen, C₁₋₆alkyl, C₂₋₆alkyl substituted with hydroxyl, C₁₋₆alkoxy, orhalogen, or R¹², R¹³, and the intervening nitrogen atom can form aheterocyclic ring selected from morpholine, thiomorpholine,thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, azetidine,pyrrolidine, piperidine, piperazine, unsubstituted or substituted withC₁₋₄alkyl or C₁₋₄alkyl substituted with hydroxy or C₁₋₄alkoxy; R¹⁴ andR¹⁵ are independently selected from hydrogen, C₁₋₆alkyl, hydroxyl,C₁₋₆alkoxy, C₂₋₆alkyl substituted with hydroxyl, C₁₋₆alkoxy, halogen ora heterocyclic ring selected from pyrrolidin-2-yl, imidazo-2-yl,imidazo-4-yl, morpholin-3-yl, oxazolyl, isoxazolyl, thiazolyl,tetrazolyl, which can be unsubstituted or substituted with C₁₋₄alkyl, orR¹⁴, R¹⁵, and the intervening nitrogen atom can form a heterocyclic ringselected from morpholine, thiomorpholine, thiomorpholine 1-oxide,thiomorpholine 1,1-dioxide, azetidine, pyrrolidine, piperidine,piperazine, unsubstituted or substituted with C₁₋₄alkyl or C₁₋₄alkylsubstituted with hydroxy or C₁₋₄alkoxy; R¹⁶ is chosen from no atom,hydrogen, C₁₋₆alkyl, or C₁₋₆alkyl substituted with halogen, HO, orC₁₋₆alkoxy; ---═double or single bond in the oxazole ring; when R¹⁶ isno atom, --- is a double bond, and when --- is a single bond, R⁷is Q,where Q is oxygen, sulfur, or NR¹ attached to the oxazole ring by adouble bond; m is 0-2; A is N or CH; X and Y are either N or C, whereinX and Y cannot be the same; and the dashed bonds in this ring denote asuitably appointed single and double bond; and pharmaceuticallyacceptable salts, solvates, or prodrugs thereof.
 11. The compound ofclaim 10, wherein for Formula l: A═N; X═N; Y═C; and --- in the oxazolering is a double bond; and pharmaceutically acceptable salts, solvatesand prodrugs thereof.
 12. The compound of claim 11, wherein for FormulaI: R¹, R²═H.
 13. The compound of claim 12, wherein for Formula I:R³=methyl.
 14. A compound selected from the group consisting of:(S)-2-[7-(Methoxymethyl)-1H-pyrazolo[3,4-e]benzoxazol-1-yl]-1-methylethylamine;1-[(S)-2-Aminopropyl]-1H-pyrazolo[3,4-e]benzoxazole -7-carboxylic acidamide; 1-[(S)-2-Aminopropyl]-1H-pyrazolo[3,4-e]benzoxazole -7-carboxylicacid methylamide; and pharmaceutically acceptable salts, solvates andprodrugs thereof.
 15. A topical ophthalmic composition comprising apharmaceutically effective amount of a compound in an ophthalmicallyacceptable vehicle, wherein the compound is of Formula I:

Wherein R¹ and R² are independently chosen from hydrogen, C₁₋₄alkyl; R³is selected from hydrogen, C₁₋₄alkyl, or R² and R³ can complete apyrrolidine or piperidine ring, which can be substituted with C₁₋₄alkyl;R⁴ is hydrogen, C₁₋₄alkyl, or when Y is carbon R⁴ can also be halogen;R⁵ and R⁶ are independently chosen from hydrogen, halogen, C₁₋₆alkyl,C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfoxide, nitrile, C₁₋₆alkylsubstituted with halogen; R⁷ is chosen from C═OR⁹, S(O)_(m)R¹⁰,NR¹—(C═O)—R¹¹, C₁₋₆alkyl substituted with: hydroxyl, C₁₋₆alkoxy,NR¹²R¹³, CO₂H, CO₂C₁₋₆alkyl, C(═O)NR¹²R¹³ or S(O)_(m)NR¹²R¹³, or asaturated or unsaturated 5 or 6-membered heterocyclic ring which cancontain 1-4 heteroatoms selected from N, O, or S and can beunsubstituted or substituted with C₁₋₄alkyl; or R⁷ can be chosen from aheterocyclic ring selected from oxazol-2-yl, 4,5-dihydro-oxazol-2-yl,5,6-dihydro-[1,3]oxazin-2-yl, thiazol-2-yl, 4,5-dihydro-thiazol-2-yl,benzoxazol-2-yl, benzothiazol-2-yl, imidazol-2-yl, imidazolidin-2-yl,[1,2,4]oxadiazol-5-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-5-yl, or[1,2,4]thiadiazol-3-yl which can be unsubstituted or substituted withC₁₋₄alkyl; but R⁷ cannot be hydrogen, lower alkyl, hydroxyl, loweralkoxy, amino, mono- or di-loweralkyl amino, lower alkanoylamino, orhalogen; R⁹ is chosen from hydroxyl, C₁₋₆alkoxy, NR¹⁴R¹⁵, C₁₋₆alkyl, orC₂₋₆alkyl substituted with hydroxyl, C₁₋₆alkoxy, NR¹²R¹³, CO₂H,CO₂C₁₋₆alkyl, S(O)_(m)NR¹²R¹³, halogen, or a heterocyclic ring selectedfrom pyrrolidin-2-yl, imidazo-2-yl, imidazo-4-yl, morpholin-3-yl,oxazolyl, isoxazolyl, thiazolyl, or tetrazolyl, which can beunsubstituted or substituted with C₁₋₄alkyl; R¹⁰ is chosen from NR¹²R¹³,C₁₋₆alkyl, or C₂₋₆alkyl substituted with hydroxyl, C₁₋₆alkoxy, NR¹¹R¹²,CO₂H, CO₂C₁₋₆alkyl; R¹¹ is C₁₋₆alkyl substituted with hydroxyl,C₁₋₆alkoxy, or a saturated or unsaturated 5 or 6-membered heterocyclicring which can contain 1-4 heteroatoms selected from N, O, or S and canbe unsubstituted or substituted with C₁₋₄alkyl; R¹² and R¹³ areindependently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkyl substitutedwith hydroxyl, C₁₋₆alkoxy, or halogen, or R¹², R¹³, and the interveningnitrogen atom can form a heterocyclic ring selected from morpholine,thiomorpholine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide,azetidine, pyrrolidine, piperidine, piperazine, unsubstituted orsubstituted with C₁₋₄alkyl or C₁₋₄alkyl substituted with hydroxy orC₁₋₄alkoxy; R¹⁴ and R¹⁵ are independently selected from hydrogen,C₁₋₆alkyl, hydroxyl, C₁₋₆alkoxy, C₂₋₆alkyl substituted with hydroxyl,C₁₋₆alkoxy, halogen or a heterocyclic ring selected frompyrrolidin-2-yl, imidazo-2-yl, imidazo4-yl, morpholin-3-yl, oxazolyl,isoxazolyl, thiazolyl, tetrazolyl, which can be unsubstituted orsubstituted with C₁₋₄alkyl, or R¹⁴, R¹⁵, and the intervening nitrogenatom can form a heterocyclic ring selected from morpholine,thiomorpholine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide,azetidine, pyrrolidine, piperidine, piperazine, unsubstituted orsubstituted with C₁₋₄alkyl or C₁₋₄alkyl substituted with hydroxy orC₁₋₄alkoxy; R¹⁶ is chosen from no atom, hydrogen, C₁₋₆alkyl, orC₁₋₆alkyl substituted with halogen, HO, or C₁₋₆alkoxy; ---═double orsingle bond in the oxazole ring; when R¹⁶ is no atom, --- is a doublebond, and when --- is a single bond, R⁷ is Q, where Q is oxygen, sulfur,or NR¹ attached to the oxazole ring by a double bond; m is 0-2; A is Nor CH; X and Y are either N or C, wherein X and Y cannot be the same;and the dashed bonds in this ring denote a suitably appointed single anddouble bond; and pharmaceutically acceptable salts, solvates, orprodrugs thereof.
 16. The ophthalmic composition of claim 15, whereinfor the compound of Formula I: A═N; X═N; Y═C; and --- in the oxazolering is a double bond; and pharmaceutically acceptable salts, solvatesand prodrugs thereof.
 17. The ophthalmic composition of claim 16,wherein for the compound of Formula I: R¹, R²═H.
 18. The ophthalmiccomposition of claim 17, wherein for the compound of Formula I:R³=methyl.
 19. The ophthalmic composition of claim 15, wherein thecompound of Formula I is selected from the group consisting of:(S)-2-[7-(Methoxymethyl)-1H-pyrazolo[3,4-e]benzoxazol-1-yl]-1-methylethylamine;1-[(S)-2-Aminopropyl]-1H-pyrazolo[3,4-e]benzoxazole -7-carboxylic acidamide; 1-[(S)-2-Aminopropyl]-1H-pyrazolo[3,4-e]benzoxazole -7-carboxylicacid methylamide; and pharmaceutically acceptable salts, solvates andprodrugs thereof.